Because of its extraordinarily high potency in regulating diverse biochemical events vital to good health in humans, 1.alpha.,25-dihydroxy vitamin D.sub.3, also known as calcitriol or 1,25D.sub.3, has stimulated the worldwide interest of medical researchers, molecular biologists, pharmacologists, medicinal and organic chemists, and researchers in the area of products for personal care and cancer prevention and/or treatment. Its structure is shown in Formula 1. ##STR1##
A major chemical challenge has been to design and synthesize analogs of 1.alpha.,25-dihydroxy vitamin D.sub.3 that retain potent antiproliferative and pro-differentiating activities but that lack hypercalcemic activity. Such analogs should be useful in such applications as skin care, cancer prevention and chemotherapy, and for treatment of neurodegenerative and immunological diseases.
Some synthetic analogs exhibiting such selective physiological activities, like 1.alpha.,25-dihydroxy-16-ene-23-yne-26,27-hexafluorocholecalciferol developed by Hoffman-La Roche, have been shown to possess very desirable pharmacological properties. Other useful analogs have been described in U.S. Pat. Nos. 5,403,832 and 5,830,885.
Only a few 24-fluoro and 24,24-difluoro analogs of 1,25D.sub.3, having natural A-ring substituents and stereochemistry, have been synthesized. They have been shown, however, to be disappointingly similar to 1,25D.sub.3 in terms of calcemic activity. Although their binding affinity to the vitamin D receptor (VDR) is similar to that of calcitriol, such materials do have longer plasma half-lives.
Given the foregoing, it is clear that there is a continuing need to identify additional synthetic analogs of the hormone 1.alpha.,25-dihydroxy vitamin D.sub.3, which analogs selectively exhibit desirable pharmacological activities but do not exhibit hypercalcemic activity. Accordingly, it is an object of the present invention to provide novel 1,25D.sub.3 analogs which are useful for a wide variety of beneficial medicinal and/or personal care product uses but which do not exhibit undesirably high levels of calcemic activity in vivo.